CN1894210A - Prolinylarylacetamides - Google Patents

Prolinylarylacetamides Download PDF

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Publication number
CN1894210A
CN1894210A CNA2004800376989A CN200480037698A CN1894210A CN 1894210 A CN1894210 A CN 1894210A CN A2004800376989 A CNA2004800376989 A CN A2004800376989A CN 200480037698 A CN200480037698 A CN 200480037698A CN 1894210 A CN1894210 A CN 1894210A
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phenyl
compound
methylamino
chloro
dicarboxamide
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W·梅德尔斯基
C·察克拉基迪斯
D·多尔施
B·切赞内
J·格莱茨
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Novel compounds of formula (I) wherein R, R<1>, R<2>, R<3>, X, X', and Y have the meaning cited in Claim 1. Said compounds are inhibitors of coagulation factor Xa and can be used for the prophylaxis and/or therapy of thromboembolic diseases and in the treatment of tumours.

Description

Prolinylarylacetamides
The present invention relates to formula I compound
Wherein
R represent Hal ,-C ≡ C-H ,-C ≡ C-A or OA, R 1Expression H ,=O, Hal, A, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH ,=N-OA or=CF 2,
X, X ' represent CH, CHal or N each other independently of one another,
Y represents R 4Perhaps Hal,
Ph represents not to be substituted or is replaced or trisubstd phenyls by the single replacement of A, OA, OH or Hal, two,
R 2Expression H, Hal or A,
R 3Expression H or A,
R 4Expression OH, OA, A-COO-, NHA, NHAr, NAA ', Het or-NH-CHR 5-COOR 3,
R 5Expression H, A ,-CHR 3-OH, (CH 2) n-Ph, (CH 2) n-COOH, (CH 2) n-CONH 2, (CH 2) p-NH 2, (CH 2) n-NH (=NH) NH 2, (CH 2) n-Het 1Perhaps (CH 2) n-SR 3,
Het represents to have the monocycle of 1～4 N, O and/or S atom or dicyclo is saturated, unsaturated or aromatic heterocycle, it can not be substituted or by A, OH, OA, CN, COOH, COOA and/or ketonic oxygen (=O) singly replace, two replace or three replace,
Het 1Expression has the monocycle or the Bicyclic heterocycle of 1～4 N, O and/or S atom, and it can not be substituted or is replaced or three replacements by the single replacement of A, OH, OA and/or CN, two,
A, A ' expression independently of one another each other have non-branched-chain alkyl, branched-chain alkyl or the cycloalkyl of 1～12 carbon atom, and wherein 1～7 hydrogen atom can be replaced by fluorine and/or chlorine in addition,
Ar represents not to be substituted or by Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3, CON (R 3) 2, NR 3COA, NR 3CON (R 3) 2, NR 3SO 2A, COR 3, SO 2N (R 3) 2, S (O) nA ,-[C (R 3) 2] n-COOR 3Perhaps-O-[C (R 3) 2] p-COOR 3Single replacement, two replaces or trisubstituted naphthyl, xenyl or phenyl,
Hal represents F, Cl, Br or I,
N represents 0,1,2 or 3,
P represents 1,2,3,4 or 5,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
Target of the present invention is to seek the compounds with valuable character, and especially those can be used for the compound of medication preparation.
Have been found that formula I compound and salt thereof have very valuable pharmacological performance and good tolerability.Specifically, they show factor Xa-rejection and therefore can be used for opposing and prevention of thromboembolic disorders, for example restenosis and the intermittent claudication of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy (apoplexy), stenocardia, postangioplasty.
Formula I compound according to the present invention can also be the inhibitor of the proconvertin a factor, the IXa factor and zymoplasm in the blood coagulation cascade.
Fragrant amidine derivative with anti-thrombosis function is known, for example, as can be known by EP 0 540051 B1, WO 98/28269, WO 00/71508, WO 00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO 00/71515 or WO00/71516.The ring-type guanidine that is used for the treatment of thrombotic disease for example is described among the WO97/08165.Having Xa factor, to suppress active aromatic heterocycle be known, for example, and by WO 96/10022 as can be known.N-[(amino imino methyl as the replacement of Xa factor inhibitor) phenylalkyl] the azaheterocyclyl acid amides is described among the WO 96/40679.
Other carboxamide derivative by WO 02/48099 and WO 02/57236 as can be known, other pyrrolidin derivatives is described among the WO 02/100830.Other Hete rocyclic derivatives by WO03/045912 as can be known.As the pyrrolidin derivatives of endothelin-converting enzyme inhibitor as can be known by WO02/06222.
Pyrrolidin derivatives as cholecystokinin and gastrin inhibitor is described in US5, in 340,801.Other pyrrolidin derivatives by WO 01/044192 as can be known.
According to the anti-thrombosis function of The compounds of this invention and blood coagulation resisting function owing to restraining effect, or to the restraining effect of other activation serine protease (as the VIIa factor, the IXa factor or zymoplasm) to the activation blood coagulating protein enzyme that is known as Xa factor.
Xa factor is one of proteolytic enzyme that participates in complicated blood coagulation process.Xa factor promotes that thrombogen is converted into zymoplasm.Zymoplasm is split into fibrin monomer with Fibrinogen, and these monomers cause thrombotic basic contribution after crosslinked.The activation of zymoplasm can cause the generation of thrombotic disease.Yet the effect of Trombin inhibiting can suppress to participate in thrombotic fibrinous formation.
Restraining effect to zymoplasm can be by people such as for example G.F.Cousins, Circulation1996, and 94, the method that proposes among the 1705-1712 is measured.
Like this, can prevent the formation of zymoplasm to the restraining effect of Xa factor.Participate in the formation that the blood coagulation process also suppresses thrombus thus according to formula I compound of the present invention and its esters by supressor Xa.
Compound according to the present invention to the measurement of the restraining effect of Xa factor and anticoagulation and anti-thrombosis activity can by in the body of routine or in vitro method measure.Suitable method for example has, and people such as J.Hauptmann are in Thrombosis and Haemostasis1990,63, the method for describing among the 220-223.
Can be to the restraining effect of Xa factor by people such as for example T.Hara, at Thromb.Haemostas.1994,71, the method among the 314-319 is measured.
Combine the exogenous part that back proconvertin a starts coagulation cascade with tissue factor, thereby and proconvertin a promote the activation of the X factor to provide Xa factor.Therefore, the restraining effect to the VIIa factor can prevent the formation of Xa factor and prevent that thus zymoplasm subsequently from forming.
Compound according to the present invention to the measurement of the restraining effect of the VIIa factor and anticoagulation and anti-thrombosis activity can by in the body of routine or in vitro method measure.The inhibiting routine measurement method of the VIIa factor for example has, and people such as H.F.Ronning are at ThrombosisResearch 1996,84, the method for describing among the 73-81.
Factor IXa produces in endogenic coagulation cascade and thereby the activation that participates in the X factor equally provides Xa factor.Therefore, can prevent the formation of Xa factor by different way to the restraining effect of the IXa factor.
Compound according to the present invention to the measurement of the restraining effect of the IXa factor and anticoagulation and anti-thrombosis activity can by in the body of routine or in vitro method measure.Suitable method for example has, and people such as J.Chang are in Journal of Biological Chemistry 1998,273, the method for describing among the 12089-12094.
Can also be used for the treatment of tumour, tumor disease and/or metastases according to compound of the present invention.T.Taniguchi and N.R.Lemoine are in Biomed.Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic Cancer) have pointed out the dependency between the development of the tissue factor TF/VIIa factor and broad variety cancer among the 57-59.
The publication of below listing has been described TF-VII and the Xa factor inhibitor antitumor action to the broad variety tumour:
People such as K.M.Donnelly, Thromb.Haemost.1998; 79:1041-1047;
People such as E.G.Fischer, J.Clin.Invest.104:1213-1221 (1999);
People such as B.M.Mueller, J.Clin.Invest.101:1372-1378 (1998);
People such as M.E.Bromberg, Thromb.Haemost.1999; 82:88-92.
Formula I compound can be used as medicine activity component in people and veterinary drug, especially for treatment and prevention of thromboembolic disorders, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty restenosis, intermittent claudication, venous thrombosis, pulmonary infarction, artery thrombosis, myocardial ischemia, based on thrombotic unstable angina and apoplexy.
Also be used for the treatment of or the atherosis disease of prevention of arterial according to compound of the present invention, such as coronary artery disease, cerebral arterial disease or peripheral arterial disease.
In myocardial infarction, described compound also is used in combination with other thrombolytic agent, is further used for preventing inaccessible again after thrombolysis, Percutaneous Transluminal Angioplasty (PTCA) and the coronary bypass (coronary bypass operations).
Also in microsurgery, be used to prevent to form once more thrombus according to compound of the present invention, in addition also as the anti-coagulant relevant with artificial organ or in hemodialysis as anti-coagulant.
Described compound is further used for cleaning intravital conduit of patient and medical assistor, perhaps is used for external preservation blood, blood plasma and other blood products as anti-coagulant.Be used for wherein blood coagulation in addition according to compound of the present invention lysis is produced the disease that Secondary cases pathology roots have been represented in vital role or blood coagulation, for example cancer (comprising cancer metastasis), inflammatory diseases (comprising sacroiliitis) and diabetes.
According to compound of the present invention be used in addition treat migraine (people such as F.Morales-Asin, Headache, 40,2000,45-47).In addition, they can also be used for the treatment of tinnitus.The purposes of anti-coagulant in tinnitus treatment is described in InternationalTinnitus Journal (2003) by people such as R.Mora, and 9 (2), among the 109-111.
In described treatment of diseases, also be used in combination according to compound of the present invention with other thrombolysis activity compound, described other compound for example has t-PA, streptokinase or the urokinase of " tissue plasminogen activator " t-PA, modification.According to compound of the present invention can be when using described other material, before or after use.
In order to prevent thrombotic recurrence, preferred especially and Asprin is used simultaneously.
Also be used for being used in combination according to compound of the present invention with platelet glycoprotein acceptor (IIb/IIIa) antagonist of anticoagulant.
The present invention relates to formula I compound and its esters, and relate to according to the formula I compound of claim 1～16 with and the preparation method of available derivative, solvate, salt and steric isomer pharmaceutically, it is characterized in that:
A) make formula II compound
Figure A20048003769800161
Wherein R, R 1, R 2, X and X ' as defined in claim 1, with the reaction of formula III compound,
Wherein
Y and R 3As defined in claim 1,
Perhaps
B) make formula IV compound
Wherein R, R 1, R 2, R 3, X and X ' as defined in claim 1, with the reaction of formula V compound,
Figure A20048003769800172
Wherein
Y as defined in claim 1, and
L represents the OH group that Cl, Br, I or free or reactive functional are modified,
Perhaps
C) make formula VI compound
Figure A20048003769800173
Wherein
R and R 1As defined in claim 1, and
L represents the OH group that Cl, Br, I or free or reactive functional are modified, with the reaction of formula VII compound,
Figure A20048003769800174
R wherein 2, R 3, X, X ' and Y as defined in claim 1,
And/or
Alkali or the sour a kind of salt that is converted into it with formula I.
The invention still further relates to photolytic activity form (steric isomer), enantiomer, racemoid, diastereomer and the hydrate and the solvate of these compounds.The solvate of term compound means the inert solvent molecule and adds and be incorporated into the adducts that forms on the described compound, and this power of attracting each other owing to them forms.Solvate has, for example monohydrate, dihydrate or alcohol adduct.
Term pharmaceutically available derivative means, for example, and according to the salt and the so-called preceding drug compound of The compounds of this invention.
The term prodrug derivant means, and with the formula I compound that for example alkyl or carboxyl groups, sugar or oligopeptides are modified, they are cracking rapidly in organism, thereby forms according to active compound of the present invention.
These prodrug derivants also comprise the biodegradable polymer derivant according to compound of the present invention, as Iht.J.Pharm. 115, described in the 61-67 (1995).
The invention still further relates to the mixture according to formula I compound of the present invention, the mixture of two kinds of diastereomers for example is two kinds of non-enantiomer mixtures of 1: 1,1: 2,1: 3,1: 4,1: 5,1: 10,1: 100 or 1: 1000 as ratio.These are mixtures of particularly preferred Stereoisomeric compounds.
For occur more than once group, A for example, their implication is independent of each other.
In context, unless stated otherwise, group or parameters R, R 1, R 2, R 3, X, X ' and Y have defined implication in the formula I situation.
A represents alkyl, is non-side chain (straight chain) or branched-chain alkyl, and has 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atom.A preferably represents methyl, also has ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl, also has amyl group, 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group is also preferably represented for example trifluoromethyl.A is the representative ring alkyl also.
The preferred representative ring propyl group of cycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.
Therefore, A preferably also represents cyclopentyl-methyl, cyclohexyl methyl, A very particularly preferably represents to have the alkyl of 1,2,3,4,5 or 6 carbon atom, be preferably methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, trifluoromethyl, pentafluoroethyl group or 1,1, the 1-trifluoroethyl.
Alkylidene group is preferably represented methylene radical, ethylidene, propylidene, butylidene, pentylidene or hexylidene, also has branched alkylidene.
R preferably represent Hal or-C ≡ C-H.
R 1Preferred expression H ,=O (ketonic oxygen), Hal, A, OH or OA, be preferably OH especially.
R 2Preferred expression H or Hal.
X preferably represents CH or N;
X ' preferably represents CH.
R 3The preferred alkyl of representing H or having 1,2,3,4,5 or 6 carbon atom.
R 5Preferred expression H or A.
Unsubstituted Het represents, for example, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5- azoles base, 3-, the different  azoles of 4-or 5-base, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidyl, be preferably 1,2,3-triazoles-1-in addition,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or-the 5-base, 1-or 5-tetrazyl, 1,2,3- diazole-4-or-the 5-base, 1,2,4- diazole-3-or-the 5-base, 1,3,4-thiadiazoles-2-or-the 5-base, 1,2,4-thiadiazoles-3-or-the 5-base, 1,2,3-thiadiazoles-4-or-the 5-base, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 4-or 5-pseudoindoyl, 1-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 4-, 5-, 6-or 7-benzoxazol base, 3-, 4-, 5-, 6-or 7-benzisoxa  azoles base, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazole base, 4-, 5-, 6-or 7-benzo-2,1,3- di azoly, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolines base, 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-phendioxin, 4- piperazine base, in addition more preferably 1,3-benzodioxole-5-base, 1,4-benzo two  alkane-6-base, 2,1,3-diazosulfide-4-or-5-base or 2,1,3-benzo  diazole-5-base.
Described heterocyclic group also can be by some or all of hydrogenation.
Therefore unsubstituted Het can also represent, for example, 2,3-one dihydro-2-,-3-,-4-or-the 5-furyl, 2,5-dihydro-2-,-3-,-4-or 5-furyl, tetrahydrochysene-2-or-the 3-furyl, 1,3-dioxolane-4-base, tetrahydrochysene-2-or-the 3-thienyl, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl, 2,5-dihydro-1-,-2-,-3-, 4-or-the 5-pyrryl, 1-, 2-or 3-pyrrolidyl, tetrahydrochysene-1-,-2-or-the 4-imidazolyl, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrazolyl, tetrahydrochysene-1-,-3-or-the 4-pyrazolyl, 1,4-dihydro-1-,-2-,-3-or-the 4-pyridyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-or-the 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydrochysene-2-,-3-or-the 4-pyranyl, 1,4-two  alkyl, 1,3-two  alkane-2-,-4-or-the 5-base, six hydrogen-1-,-3-or-the 4-pyridazinyl, six hydrogen-1-,-2-,-4-or-the 5-pyrimidyl, 1-, 2-or 3-piperazinyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-,-6-,-7-or-the 8-quinolyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-,-6-,-7-or-the 8-isoquinolyl, 2-, 3-, 5-, 6-, 7-or 8-3,4-dihydro-2H-phendioxin, 4- piperazine base, preferred in addition 2, the 3-methylenedioxyphenyl, 3, the 4-methylenedioxyphenyl, 2,3-ethylenedioxy phenyl, 3,4-ethylenedioxy phenyl, 3,4-(difluoro methylene-dioxy) phenyl, 2,3-Dihydrobenzofuranes-5-or 6-base, 2,3-(2-oxo methylene-dioxy) phenyl or be 3,4-dihydro-2H-1,5-benzo dioxane heptene (dioxepin)-6-or-the 7-base, preferred in addition 2,3-dihydro benzo furyl or 2,3-dihydro-2-oxo-furyl.
Het preferably represents to have saturated, the unsaturated or aromatic heterocycle of monocycle of 1～2 N and/or O atom, and it can not be substituted or is replaced or three replacements by A, OH and/or the single replacement of OA, two.
Het especially preferably represents furyl, thienyl, pyrryl, imidazolyl, pyridyl, pyrimidyl, pyrazolyl, thiazolyl, indyl, pyrrolidyl, piperidyl, morpholinyl or piperazinyl, and they are not substituted separately or are replaced or three replacements by A, OH and/or the single replacement of OA, two.
Het very particularly preferably represents imidazolyl, pyridyl, piperidyl, morpholinyl or piperazinyl, and they are not substituted separately or are replaced or three replacements by A, OH and/or the single replacement of OA, two.
Unsubstituted Het 1Preferred expression, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5- azoles base, 3-, the different  azoles of 4-or 5-base, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidyl are preferably 1 in addition, 2,3-triazole-1-,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or-the 5-base, 1-or 5-tetrazyl, 1,2,3- diazole-4-or-the 5-base, 1,2,4- diazole-3-or-the 5-base, 1,3,4-thiadiazoles-2-or-the 5-base, 1,2,4-thiadiazoles-3-or-the 5-base, 1,2,3-thiadiazoles-4-or-the 5-base, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 4-or 5-pseudoindoyl, 1-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 4-, 5-, 6-or 7-benzoxazol base, 3-, 4-, 5-, 6-or 7-benzisoxa  azoles base, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazole base, 4-, 5-, 6-or 7-benzo-2,1,3- di azoly, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolines base, 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-phendioxin, 4- piperazine base, in addition more preferably 1,3-benzodioxole-5-base, 1,4-benzo two  alkane-6-base, 2,1,3-benzo-thiadiazoles-4-or-5-base or 2,1,3-benzo  diazole-5-base.
Het 1Preferred especially expression has the unsubstituted monocycle or the Bicyclic heterocycle of 1～2 N, O and/or S atom; Very particularly preferably represent thienyl, furyl, imidazolyl or indyl.
Ar represents, phenyl for example, adjacent-, between-or right-tolyl, adjacent-, between-or right-ethylphenyl, adjacent-, between-or right-propyl group phenyl, adjacent-, between-or right-isopropyl phenyl, adjacent-, between-or right-tert-butyl-phenyl, adjacent-, between-or right-hydroxy phenyl, adjacent-, between-or right-nitrophenyl, adjacent-, between-or right-aminophenyl, adjacent-, between-or right-(N-methylamino) phenyl, adjacent-, between-or right-(N-methylamino carbonyl) phenyl, adjacent-, between-or right-acetylamino phenyl, adjacent-, between-or right-p-methoxy-phenyl, adjacent-, between-or right-ethoxyl phenenyl, adjacent-, between-or right-ethoxy carbonyl phenyl, adjacent-, between-or right-(N, the N-dimethylamino) phenyl, adjacent-, between-or right-(N, N-dimethylamino carbonyl) phenyl, adjacent-, between-or right-(N-ethylamino) phenyl, adjacent-, between-or right-(N, N-diethylamino) phenyl, adjacent-, between-or right-fluorophenyl, adjacent-, between-or right-bromophenyl, adjacent-, between-or right-chloro-phenyl-, adjacent-, between-or right-(sulfonyloxy methyl amino) phenyl, adjacent-, between-or right-(methyl sulphonyl) phenyl, preferably represent 2 in addition, 3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3, the 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3, the 5-dibromo phenyl, 2,4-or 2,5-dinitrophenyl, 2,5-or 3,4-Dimethoxyphenyl, 3-nitro-4-chloro-phenyl-, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chloro-phenyl-, 2-nitro-4-N, the N-dimethylamino-or 3-nitro-4-N, the N-dimethylaminophenyl, 2, the 3-diamino-phenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6-or 3,4, the 5-trichlorophenyl, 2,4, the 6-trimethoxyphenyl, 2-hydroxyl-3, the 5-dichlorophenyl, right-iodophenyl, 3,6-two chloro-4-aminophenyls, 4-fluoro-3-chloro-phenyl-, 2-fluoro-4-bromophenyl, 2,5-two fluoro-4-bromophenyls, 3-bromo-6-p-methoxy-phenyl, 3-chloro-6-p-methoxy-phenyl, 3-chloro-4-acetylamino phenyl, 3-fluoro-4-p-methoxy-phenyl, 3-amino-6-aminomethyl phenyl, 3-chloro-4-acetylamino phenyl or 2,5-dimethyl-4-chloro-phenyl-; Also have unsubstituted naphthyl or xenyl.
Ar especially preferably represents not to be substituted or by Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3Perhaps CON (R 3) 2Single replacement, two replaces or trisubstituted naphthyl or phenyl.Ar very particularly preferably represents phenyl.
Described formula I compound can have one or more chiral centres, and therefore can exist with multiple stereoisomer form.Described formula I comprises all these forms.
In view of the above, The present invention be more particularly directed to wherein, at least one described group has a kind of formula I compound of preferred meaning as mentioned above.Some preferred compound groups can be represented that these minors are consistent with formula I and wherein do not have more detailed specified group to have defined implication in the formula I situation by following minor Ia～Io, but wherein:
In Ia R represent Hal or-C ≡ C-H;
R in Ib 1Expression H ,=O, Hal, A, OH or OA;
R in Ic 1Expression OH;
X represents CH or N in Id,
X ' expression CH;
R in Ie 2Expression H or Hal;
R in If 3Expression H or have the alkyl of 1,2,3,4,5 or 6 carbon atom;
Het represents to have saturated, the unsaturated or aromatic heterocycle of monocycle of 1～2 N and/or O atom in Ig, and it can not be substituted or is replaced or three replacements by A, OH and/or the single replacement of OA, two;
Het represents furyl, thienyl, pyrryl, imidazolyl, pyridyl, pyrimidyl, pyrazolyl, thiazolyl, indyl, pyrrolidyl, piperidyl, morpholinyl or piperazinyl in Ih, and they are not substituted separately or are replaced or three replacements by A, OH and/or the single replacement of OA, two;
Het in Ii 1Expression has the unsubstituted monocycle or the Bicyclic heterocycle of 1～2 N, O and/or S atom;
R in Ij 5Expression H or A;
Ar represents not to be substituted or by Hal, A, OR in Ik 3, N (R 3) 2, NO 2, CN, COOR 3Perhaps CON (R 3) 2Single replacement, two replaces or trisubstituted naphthyl or phenyl;
Ar represents phenyl in Il;
In Im R represent Hal or-C ≡ C-H,
R 1Expression OH,
X represents CH or N,
X ' expression CH,
Y represents R 4Perhaps Hal,
R 2Expression H or Hal,
R 3Expression has the alkyl of 1,2,3,4,5 or 6 carbon atom,
R 4Expression OH, OA, A-COO-, NHA, NHAr, NAA ', Het ,-NH-CHR 5-COOR 3Perhaps-NH-CHR 5-COOH,
R 5Expression H or A,
Het represents to have saturated, the unsaturated or aromatic heterocycle of monocycle of 1～2 N and/or O atom, and it can not be substituted or is replaced or three replacements by A, OH and/or the single replacement of OA, two,
A, A ' expression independently of one another each other have non-branched-chain alkyl, branched-chain alkyl or the cycloalkyl of 1～12 carbon atom, and wherein 1～7 hydrogen atom can be replaced by fluorine and/or chlorine in addition,
Hal represents F, Cl, Br or I,
N represents 0,1,2 or 3,
P represents 1,2,3,4 or 5;
In In according to one or multinomial formula Ia compound in the claim 1～14,
Figure A20048003769800231
Wherein
R represent Hal or-C ≡ C-H,
R 1Expression OH,
X represents CH or N,
X ' expression CH,
Y represents R 4Perhaps Hal,
R 2Expression H or Hal,
R 3Expression has the alkyl of 1,2,3,4,5 or 6 carbon atom,
R 4Expression OH, OA, A-COO-, NHA, NAA ', Het ,-NH-CHR 5-COOR 3
Perhaps-NH-CHR 5-COOH,
R 5Expression H or A,
Het represents to have saturated, the unsaturated or aromatic heterocycle of monocycle of 1～2 N and/or O atom, and it can not be substituted or is replaced or three replacements by A, OH and/or the single replacement of OA, two,
A, A ' expression independently of one another each other have non-branched-chain alkyl, branched-chain alkyl or the cycloalkyl of 1～12 carbon atom, and wherein 1～7 hydrogen atom can be replaced by fluorine and/or chlorine in addition, perhaps replaced by F, Cl, Br or I,
Hal represents F, Cl, Br or I,
N represents 0,1,2 or 3,
P represents 1,2,3,4 or 5;
In Io according to one or multinomial formula Ia compound in the claim 1～14
Wherein
R represent Hal or-C ≡ C-H,
X ' expression OH,
X represents CH or N,
X ' expression CH,
Y represents R 4Perhaps Hal,
R 2Expression H or Hal,
R 3Expression has the alkyl of 1,2,3,4,5 or 6 carbon atom,
R 3' expression methyl,
R 4Expression OH, OA, A-COO-, NHA, NAA ', Het ,-NH-CHR 5-COOR 3
Perhaps-NH-CHR 5-COOH,
R 5Expression H or A,
Het represents furyl, thienyl, pyrryl, imidazolyl, pyridyl, pyrimidyl, pyrazolyl, thiazolyl, indyl, pyrrolidyl, piperidyl, morpholinyl or piperazinyl, they are not substituted separately or are replaced or three replacements by A, OH and/or the single replacement of OA, two
A, A ' expression independently of one another each other have non-branched-chain alkyl, branched-chain alkyl or the cycloalkyl of 1～12 carbon atom, and wherein 1～7 hydrogen atom can be replaced by fluorine and/or chlorine in addition, perhaps replaced by F, Cl, Br or I,
Hal represents F, Cl, Br or I,
N represents 0,1,2 or 3,
P represents 1,2,3,4 or 5;
With and pharmaceutically available derivative, solvate and steric isomer thereof, comprise the mixture of their various ratios.
In addition, formula I compound and preparation raw material thereof all are prepared by self known method, as document (for example in classic, Houben-Weyl for example, the vitochemical method of Methoden derorganischen Chemie[], Georg-Thieme-Verlag, Stuttgart) described in, known and be applicable under the reaction conditions of described reaction and accurately carry out.Mutation that also can the currently known methods of use own is here carried out, but does not narrate in more detail at this.
If expectation, described raw material can also original position form, thereby need not they are separated from reaction mixture, but they further is converted into formula I compound immediately.
Usually formula II, III, IV, V, VI and VII starting compound are known.
Formula I compound can preferably obtain by formula II compound and formula III compound are reacted.Described reaction is preferably at Ullmann reaction conditions (Cul, K 2CO 3, DMSO, 130 °) under carry out, perhaps particularly preferably in carrying out under the Buchwald amidation condition (J.Am.Chem.Soc.2002,121,7421).
This reaction is usually in inert solvent, in the presence of acid binding agent (an acid-binding agent), carry out, described acid binding agent is preferably oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal, perhaps other salt of weak acid of basic metal or alkaline-earth metal, preferred potassium, sodium, calcium or caesium.The adding of organic bases (for example triethylamine, xylidine, N, N '-dimethylene diamines, pyridine or quinoline) also suits.Depend on used condition, the reaction times is several minutes to 14 day, and temperature of reaction is about 0 °～150 °, is generally 20 °～130 °, is preferably 60 °～90 ° especially.
The example of suitable inert solvent is a hydro carbons, for example hexane, sherwood oil, benzene, toluene or dimethylbenzene; Chlorinated hydrocarbons, trieline, 1 for example, 2-ethylene dichloride, tetrachloromethane, chloroform or methylene dichloride; Alcohols, for example methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or the trimethyl carbinol; Ethers, for example ether, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) or dioxane; Glycol ethers, for example ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, glycol dimethyl ether (diglyme); Ketone, for example acetone or butanone; Amides, for example ethanamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF); Nitrile, for example acetonitrile; Sulfoxide class, for example methyl-sulphoxide (DMSO); Dithiocarbonic anhydride; Carboxylic-acid, for example formic acid or acetate; Nitro-compound, for example Nitromethane 99Min. or oil of mirbane; Ester class, for example ethyl acetate; The perhaps mixture of described solvent.
In addition, formula I compound can preferably obtain by formula IV compound and formula V compound are reacted.In formula V compound, L preferably represents Cl, Br, I or the reactive OH group of modifying, for example activatory ester, imidazoline amide (imidazolide) or have the alkylsulfonyloxy (preferable methyl sulfonyloxy or trifluoromethyl sulfonyloxy) of 1～6 carbon atom or have the aryl-sulfonyl oxygen (preferred phenyl sulfonyloxy or right-tolylsulfonyl-oxygen base) of 6～10 carbon atoms.
This type of group of activated carboxyl (for example has been described in the document in typical acylation reaction, at classic, Houben-Weyl for example, the vitochemical method of Methoden der organischenChemie[], Georg-Thieme-Verlag, Stuttgart; ).
The activatory ester can advantageously form in position, for example by adding HOBt or N-hydroxy-succinamide.
This reaction is usually in inert solvent, in the presence of acid binding agent, carry out, described acid binding agent is preferably oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal, perhaps other salt of weak acid of basic metal or alkaline-earth metal, preferred potassium, sodium, calcium or caesium.Organic bases, for example triethylamine, xylidine, pyridine or quinoline, the adding of perhaps excessive formula IV amine component also is favourable.Depend on used condition, the reaction times is several minutes～14 day, and temperature of reaction is about 0 °～150 °, is generally 20 °～130 °.Suitable inert solvent is those above-mentioned inert solvents.
In addition, formula I compound can preferably obtain by formula VI compound and formula VII compound are reacted.In formula VI compound, L preferably represents Cl, Br, I or the reactive OH group of modifying, for example activatory ester, imidazoline amide or have the alkylsulfonyloxy (preferable methyl sulfonyloxy or trifluoromethyl sulfonyloxy) of 1～6 carbon atom or have the aryl-sulfonyl oxygen (preferred phenyl sulfonyloxy or p-methylphenyl sulfonyloxy) of 6～10 carbon atoms.
This type of group of activated carboxyl (for example has been described in document in typical acylation reaction, at classic, Houben-Weyl for example, the vitochemical method of Methoden der organischenChemie[], Georg-Thieme-Verlag, Stuttgart; ) in.
Acibenzolar can advantageously form in position, for example by adding HOBt or N-hydroxy-succinamide.
This reaction is usually in inert solvent, in the presence of acid binding agent, carry out, described acid binding agent is preferably oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal, perhaps other salt of weak acid of basic metal or alkaline-earth metal, preferred potassium, sodium, calcium or caesium.Organic bases, for example triethylamine, xylidine, pyridine or quinoline, the adding of perhaps excessive formula VII amine component also is favourable.Depend on used condition, the reaction times is several minutes～14 day, and temperature of reaction is about 0 °～150 °, is generally 20 °～130 °.Suitable inert solvent is those above-mentioned inert solvents.
Medicinal salts and other form
Compound according to the present invention can be used with their final salt-independent shape.On the other hand, the present invention also comprises the form application of these compounds with their pharmacy acceptable salt classes, and described pharmacy acceptable salt class can be derived by methods known in the art by various organic and inorganic bronsted lowry acids and bases bronsted lowries and be obtained.Formula I compound pharmacy acceptable salt form major part is prepared by ordinary method.If formula I compound comprises carboxylic group, its a kind of suitable salt can form in the following manner: this compound and the alkali that is fit to are reacted, thereby provide corresponding base addition salt.Such alkali is that for example alkali metal hydroxide comprises potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides, for example hydrated barta and calcium hydroxide; Alkali metal alcoholates, for example potassium ethylate and sodium propylate; With multiple organic bases, for example piperidines, diethanolamine and N-methyl glutamine.The aluminium salt of formula I compound is included too.In the situation of some formula I compound, its acid salt can be by forming with pharmaceutically acceptable organic and these compounds of mineral acid treatment, described organic and mineral acid is, for example hydrogen halide (hydrogenchloride for example, hydrogen bromide or hydrogen iodide), other mineral acid and corresponding salt thereof (vitriol for example, nitrate or phosphoric acid salt or the like) and alkyl or single salt aryl sulfonate (esilate for example, tosylate and benzene sulfonate) and other organic acid and corresponding salt thereof (acetate for example, trifluoroacetate, tartrate, maleate, succinate, Citrate trianion, benzoate, salicylate and ascorbate salt or the like).By this, formula I compound pharmaceutically-acceptable acid addition comprises following these salts: acetate, adipate, alginate, arginic acid salt (arginate), aspartate, benzoate, benzene sulfonate (besylate), hydrosulfate, hydrosulphite, bromide, butyrates, camphorate, camsilate, octylate, muriate, chloro-benzoate, Citrate trianion, cyclopentane propionate, digluconate, dihydrogen orthophosphate, dinitro-benzoate, dodecyl sulfate, esilate, fumarate, mutate (from tetrahydroxyadipic acid), the galacturonic hydrochlorate, the glucose enanthate, gluconate, glutaminate, glycerophosphate, hemisuccinic acid salt, Hemisulphate, enanthate, hexanoate, hippurate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, iodide, isethionate, isobutyrate, lactic acid salt, Lactobionate (lactobionate), malate, maleate, malonate, mandelate, metaphosphate, mesylate, tolyl acid salt, one hydrogen orthophosphate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmitate, pectate (pectinate), persulphate, phenylacetic acid salt, 3-phenylpropionic acid salt, phosphoric acid salt, phosphonate, phthalate, but this does not represent limitation ot it.
In addition, comprise aluminium, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salt, but this is not intended expression and limits it according to the alkali salt class of The compounds of this invention.In above-mentioned salt, be preferably ammonium salt; Sodium in the alkaline metal salt and sylvite; With calcium and the magnesium salts in the alkaline-earth metal salt.The salt that is derived from the formula I compound of pharmaceutically acceptable organic nontoxic alkali class comprises the salt of following alkali: primary amine, secondary amine and tertiary amine, the amine that replaces, also comprise naturally occurring substitutional amine-group, cyclammonium class and deacidite class, arginine for example, trimethyl-glycine, caffeine, chloroprocaine, choline, N, N '-dibenzyl-ethylenediamin (benzyl star), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, thanomin, quadrol, N-ethylmorpholine, N-ethyl-piperidines, glycosamine (glucamine), glucosamine (glucosamine), Histidine, breathe out amine (hydrabamine), isopropylamine, lignocaine, Methionin, meglumine (meglumine), N-methyl D-glycosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, the purine class, Theobromine, trolamine, triethylamine, Trimethylamine 99, tripropyl amine and trihydroxymethylaminomethane (tromethane), but this does not represent limitation ot it.
It is quaternized that the The compounds of this invention that contains alkaline nitrogen-containing group can use following reagent to carry out: (C for example 1-C 4) alkyl halide, for example methyl, ethyl, sec.-propyl and t butyl chloride, bromide and iodide; Two (C 1-C 4) alkyl-sulphate, for example dimethyl, diethyl and diamyl vitriol; (C 10-C 18) alkyl halide, for example decyl, dodecyl, lauryl, tetradecyl and octadecyl chlorination thing, bromide and iodide; And aryl (C 1-C 4) alkyl halide, for example benzyl chloride and phenethyl bromide.Water-soluble and oil-soluble compounds according to the present invention can use such salt to be prepared.
Above-mentioned pharmaceutical salts preferably includes acetate, trifluoroacetate, benzene sulfonate, Citrate trianion, fumarate, gluconate, hemisuccinic acid salt, hippurate, hydrochloride, hydrobromate, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate salt, stearate, vitriol, sulfosalicylate, tartrate, Thiomalate, tosylate and tromethane (tromethamine), but this does not mean the qualification to it.
The acid salt class of the basic cpd of formula I can prepare in the following manner: the compound of free alkali form is contacted with the described acid of fully measuring, make described salt form in a usual manner.This free alkali can form in the following manner again: described salt form is contacted with alkali, and separated free alkali in a usual manner.Aspect some physicals (for example solubleness in polar solvent), its corresponding in some aspects salt form difference of described free alkali form; Yet, for the object of the invention, described salt in others corresponding to its corresponding free alkali form.
As mentioned above, for example basic metal and alkaline-earth metal or organic amine form the pharmaceutically acceptable base addition salt class of formula I compound with metal or amine.Preferred metal is sodium, potassium, magnesium and calcium.Preferred organic amine is N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-methyl D-glycosamine and PROCAINE HCL, PHARMA GRADE.
The base addition salt class of acidic cpd can prepare in the following manner according to the present invention: the compound of free acid form is contacted with the described alkali of fully measuring, make described salt form in a usual manner.This free acid can form in the following manner again: described salt form is contacted with acid, and separated free acid in a usual manner.Aspect some physicals (for example solubleness in polar solvent), its corresponding in some aspects salt form difference of described free acid form; Yet, for the object of the invention, described salt in others corresponding to its corresponding free acid form.
If compound according to the present invention contains the group that can form this type pharmacy acceptable salt class more than, the present invention also comprises these many salt so.General many salt forms comprise, for example bitartrate (bitartrate), diacetate, two fumarate (difumarate), two meglumine (dimeglumine), diphosphate, disodium salt and tri hydrochloride, but this does not represent limitation ot it.
According to as mentioned above as can be seen, in the application's context, word " pharmacy acceptable salt " means the activeconstituents of the form of one of salt of comprising with formula I compound, if particularly compare with other salt form of the free form of this activeconstituents or previous used this activeconstituents, this salt form can provide the activeconstituents with improved pharmacokinetic property.The pharmacy acceptable salt form of this activeconstituents also provides the pharmacokinetic property of the expectation that this activeconstituents do not have in the past first, and result of treatment aspect in vivo, it in addition can have positive influence to the pharmacodynamics of this activeconstituents.
Because their molecular structure, formula I compound according to the present invention may be a chirality, and correspondingly can have multiple enantiomeric forms.Therefore they can exist with racemic form or optically-active form.
Because the pharmaceutical active according to the racemoid of The compounds of this invention or steric isomer may be different, therefore wish to use enantiomer.In this case, end product or even intermediate can by chemistry well known to those skilled in the art or physical method for separation be the enantiomerism compound or even use it for synthetic in.
In the situation of racemic amines class, diastereomer is formed by reacting with the optically-active resolving agent by described mixture.The example of suitable resolving agent is the opticity acids; as the amino acid (for example N-benzoyl proline(Pro) or N-benzenesulfonyl proline(Pro)) of the tartrate of R and S form, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid, suitable N-protected, perhaps the camphorsulfonic acid class of various opticities.Splitting enantiomer by optically-active resolving agent (other derivative of dinitrobenzoyl phenylglycocoll, cellulosic triacetate or carbohydrate for example perhaps is fixed on chirality on the silica gel methacrylate polymers of deriving) chromatography also is advantageously.The example that is suitable for the eluent of this purpose is moisture or contains the solvent mixture of alcohol, hexane/isopropyl alcohol/acetonitrile for example, and for example ratio is 82: 15: 3.
The present invention relates to formula I compound in addition and/or its pharmacy acceptable salt is used to prepare medicine (pharmaceutical composition), particularly prepares the purposes of medicine by method non-chemically.They can be converted into suitable formulation with at least a solid, liquid and/or semi-fluid vehicle or auxiliary at this, and if expectation, they can make up with one or more other activeconstituentss.
The present invention relates to medicine in addition, comprises at least a formula I compound and/or its pharmaceutically available derivative, solvate and steric isomer, comprises the mixture of their all proportions, and optional vehicle and/or the auxiliary of comprising.
Described pharmaceutical preparation can be with the form administration of dose unit, and wherein each dose unit all comprises the activeconstituents of predetermined amount.Such dose unit can comprise, for example, 0.5mg～1g, preferred 1mg～700mg, preferred especially 5mg～100mg according to compound of the present invention, this depends on disease, medication and patient's age, body weight and the situation of treatment; Perhaps pharmaceutical preparation can be with the form administration of dose unit, and wherein each dose unit comprises the activeconstituents of predetermined amount.The preferred dosage unit formulation is to comprise per daily dose or part dosage, the perhaps dosage unit preparations of the activeconstituents of its corresponding section as mentioned above.In addition, such pharmaceutical preparation can use the method for pharmaceutical field common general knowledge to be prepared.
Can make pharmaceutical preparation being suitable for, for example by the medication that (comprises subcutaneous, intramuscular, vein or intracutaneous) outside oral (comprising cheek or hypogloeeis), rectum, nose, part (comprise cheek, hypogloeeis or through skin), vagina or the enteron aisle by any desired appropriate methodology administration.Such preparation can use all known methods of pharmaceutical field to be prepared, for example, and with this activeconstituents and vehicle or auxiliary combination.
The medicinal preparations that is suitable for oral administration can have for example capsule or tablet with the administration of isolating unit; Pulvis or granule; Solution or suspensoid in water or the non-aqueous fluid; Edible foam or foam food prods; Perhaps oil-in-water liquid emulsion or water-in-oil liquid emulsion.
Therefore, for example in the situation with tablet or capsule form oral administration, active ingredient components can for example ethanol, G ﹠ W or the like make up with oral, nontoxic and pharmaceutically acceptable inert excipient.Pulvis can prepare by compound powder being broken to suitable fine size and it being mixed with the pharmaceutical excipient of pulverizing in a similar manner, and vehicle has for example edible carbohydrate, as for example starch or N.F,USP MANNITOL.Seasonings, sanitas, dispersion agent and dyestuff can exist equally.
Capsule is by preparing as mentioned above powdered mixture and being packed in the shaping gelatin shell and making with being about to it.Glidant and lubricant, for example the silicic acid of high dispersing, talcum, Magnesium Stearate, calcium stearate or solid polyethylene glycol can join in the powdered mixture before the filling operation.In order to improve the availability that capsule is used the back medicine, equally can be with disintegrating agent or solubilizing agent, for example agar, lime carbonate or yellow soda ash add wherein.
In addition, if expectation or needs, suitable tackiness agent, lubricant and disintegrating agent and dyestuff can mix in the described mixture equally.Sweeting agent, natural and synthetic rubber (for example gum arabic, tragakanta or sodiun alginate, carboxymethyl cellulose, polyoxyethylene glycol and wax or the like) that suitable tackiness agent comprises starch, gelatin, natural sugar (for example glucose or beta lactose), made by corn.The lubricant that is used for these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate and sodium-chlor or the like.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, bentonite and xanthan gum or the like.Described tablet can be prepared by for example following method: the preparation powdered mixture, this mixture of granulation or dry-pressing adds lubricant and disintegrating agent and suppresses whole mixture, thereby obtains tablet.The compound that powdered mixture can be pulverized with suitable way mixes and prepares with thinner or matrix as mentioned above, and optional with tackiness agent (for example carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone), dissolve retarding agent (for example paraffin), absorption enhancer (for example quaternary salt) and/or absorption agent (for example bentonite, kaolin or Lin Suanergai) and mix.Described powdered mixture can carry out granulation in the following manner: with tackiness agent that it is wetting and it is pressed through screen cloth, tackiness agent is the solution of syrup, starch paste, Acadia's glue (acadia mucilage) or Mierocrystalline cellulose or polymkeric substance for example.As a kind of alternative granulating method, can make powdered mixture pass through tablets press, make the caking of the inhomogeneous shape formation particle that is broken.In order to prevent that particle from clinging the tablet draw mould, described particle can be lubricated by adding stearic acid, stearate, talcum or mineral oil.Then this lubrication mixture is suppressed, thereby provided tablet.Can also make up with the free-pouring inert excipient of energy according to compound of the present invention, directly it be suppressed then and provide tablet, and unreal granules applicationization or dry-pressing step.Can there be the transparent or opaque protective layer of forming by shellac sealer coat, sugar or polymer material layer and waxy luster layer.In order to distinguish various dose units, dyestuff can be joined in these dressings.
Liquid oral, for example solution, syrup and elixir can be prepared with the form of dose unit, make the compound that comprises predetermined amount in the specified rate.Syrup can prepare by suitable seasonings is dissolved in the compound water solution, and elixir can use nontoxic alcohols carrier to be prepared simultaneously.Suspensoid can be prepared by compound is dispersed in the non-toxic carrier.Solubilizing agent and emulsifying agent (for example ethoxylation isooctadecanol and polyoxyethylene sorbitol ether), sanitas and odor control additive (for example spearmint oil or natural sweeteners or asccharin or other artificial sweetening agent or the like) can add wherein equally.
If expectation, the oral dosage units preparation can be encapsulated in the microcapsule.Said preparation can also prepare by a kind of like this method, makes drug release be extended or postpones, for example by with among particulate matter dressing or embedded polymer thing, wax or the like.
The individual layer capsule that described formula I compound and its esters, solvate and physiology functional derivatives are can also be with the form of liposome delivery system for example little, big individual layer capsule and the administration of multilayer capsule.Liposome can be formed by multiple phosphatide, for example cholesterol, stearylamine or Yelkin TTS.
Formula I compound and its esters, solvate and physiology functional derivatives can also use monoclonal antibody to send as the individual carrier that compound molecule is coupled on it.This compound can also be bound up with the soluble polymer as the drug target carrier.Such polymkeric substance can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropylmethyl acrylamido phenol, poly-hydroxyethyl asparaginyl group phenol or the polyethylene oxide polylysine that is replaced by palmitoyl groups.In addition, this compound can be coupled to a class and be suitable for realizing on the biodegradable polymkeric substance of medicine sustained release, for example poly(lactic acid), poly--6-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydroxyl pyrans, polybutylcyanoacrylate and crosslinked or amphipathic hydrogel segmented copolymer.
In order to extend with receptor's epidermis and closely to contact, the medicinal preparations that is suitable for percutaneous dosing can be used as independently ointment administration.Thus, for example, described activeconstituents can be discharged by ointment by iontophoresis, as Pharmaceutical Research, is summarized in 3 (6), 318 (1986).
The medicinal compound that is suitable for topical can be mixed with ointment, ointment, suspensoid, lotion, pulvis, solution, paste, gelifying agent, sprays, aerosol or finish.
In order to treat eyes or other outside organization (for example mouth and skin), preferred described preparation is used with topical ointments or ointment.At preparation is in the situation of ointment, and described active ingredient can be used with the paraffin emulsifiable paste matrix or with emulsifiable paste matrix that water dissolves each other.Perhaps, can be with active ingredient with oil-in-water emulsifiable paste matrix or water-in-oil based water plasmogamy system, thus provide ointment.
The medicinal preparations that is suitable for locally applying to eyes comprises eye drops, and solubilization of active ingredient or be suspended in the suitable carrier wherein is particularly in the aqueous solvent.
Be suitable for that the medicinal preparations of topical application comprises lozenge, pastille (pastilles) and mouth-washes in mouth.
The medicinal preparations that is suitable for rectal administration can be with the form administration of suppository or enema.
Wherein carrier substance is that the medicinal preparations that solid is suitable for intranasal administration comprises dust base, the particle diameter of described dust base for example is 20～500 microns, said preparation is with the mode administration with snuffing gas, promptly by nasal passage from keeping the rapid inhalation of the container that comprises powder near nose.Use liquid to comprise the activeconstituents aqueous solution or oil solution as the suitable formulations with nasal spray or nasal drop administration of carrier substance.
Be suitable for comprising particle dust in small, broken bits or mist that it can generate by the various types of pressurization dividers that have aerosol, spraying gun or insufflator by the medicinal preparations of inhalation.
The medicinal preparations that is suitable for vagina administration can be with vaginal suppository, tampon, ointment, gelifying agent, paste, foam or spray agent administration.
The medicinal preparations that is suitable for the enteron aisle external administration comprises water-based and nonaqueous aseptic injection liquor, wherein comprises antioxidant, damping fluid, fungistat and solute, makes said preparation and receptor's blood for the treatment of etc. ooze by them; And water-based and nonaqueous aseptic suspensoid, wherein can comprise suspension medium and thickening material.Said preparation can be controlled in single dosage or the multi-dose container, for example Mi Feng ampoule and phial, and store with freeze dried (lyophilize) state, making was only needing to add sterile carrier liquid (for example, water for injection) before instant the use.
Injection liquor and suspensoid according to the prescription preparation can be by sterile powder, granule and tablet preparation.
Clearly, except the component of above-mentioned special statement, according to the particular type of preparation, said preparation can also comprise the reagent that other this area is commonly used; Therefore, for example be applicable to that oral preparation can comprise seasonings.
The treatment significant quantity of formula I compound depends on many factors, comprises the character and the medication of the accurate situation of the age of animal for example and body weight, needs treatment and its severity, preparation, and is finally determined by treatment doctor or animal doctor.Yet, be typically 0.1～100mg/kg receptor (Mammals) body weight/day according to the significant quantity of compound of the present invention, and 1～10mg/kg body weight/day particularly.Thus, the actual amount of Adult Mammals every day of body weight 70kg is generally 70～700mg, wherein this amount can or more generally be divided into a series of doses (for example being divided into twice, three times, four times, five times or six times) administration every day with single dose administration every day, makes that total per daily dose is identical.The significant quantity of its salt or solvate or physiology functional derivatives can be determined by the mark according to the significant quantity of The compounds of this invention itself.
The acceptable salt of formula I compound and physiology thereof can be used for opposing or prevention of thromboembolic disorders, for example thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or metastases.
The invention still further relates to medicine, wherein comprise at least a formula I compound and/or its pharmaceutically available derivative, solvate and steric isomer, comprise the mixture and at least a other medicines activeconstituents of its all proportions.
The invention still further relates to the packaging kit of forming by the independent packing of following substances (test kit):
(a) pharmaceutically available derivative, solvate and steric isomer of the formula I compound of significant quantity and/or its, comprise their all proportions mixture and
(b) the other medicines activeconstituents of significant quantity.
Described packaging kit comprises suitable containers, for example box, independently bottle, sack or ampoule.This test kit can, for example comprise isolating ampoule, each ampoule contains the formula I compound of significant quantity and/or its pharmaceutically available derivative, solvate and steric isomer (mixture that comprises their all proportions), and the other medicines activeconstituents of the dissolving of significant quantity or freeze-dried.
The invention still further relates to formula I compound and/or its pharmaceutically available derivative, solvate and steric isomer (mixture that comprises their all proportions) and at least a other medicines activeconstituents combination, be used for the treatment of purposes in the medicine of following disease in preparation: thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or metastases.
In context, temperature is all with a ℃ expression.In following examples, " conventional aftertreatment " is meant: add entry when needing, when needing the pH value is adjusted to 2～10, the composition that depends on end product, with ethyl acetate or the described mixture of dichloromethane extraction, to respectively be separated, organic phase is with dried over sodium sulfate and evaporate, and products therefrom obtains purifying through chromatography and/or by crystallization on silica gel.Rf is illustrated in the value on the silica gel; Eluent: ethyl acetate/methanol 9: 1.
Mass spectrum (MS): EI (electron impact ionization) M +
ESI (electron spray ionisation) (M+H) +(unless otherwise indicated)
Embodiment 1
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-dimethylamino ethanoyl) methylamino-]-phenyl)-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (" A1 ")
Figure A20048003769800361
100mg (0.351mmol) (2R; 4R)-1-(4-chloro-phenyl-formamyl)-4-hydroxyl-proline(Pro) (1) and 72.75mg (0.351mmol) N-(4-aminophenyl)-2-dimethylamino-N-methylacetamide (be described in US 2436115; 1945) be dissolved among the 1ml DMF; 62.29mg (0.351mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride is added wherein, and at room temperature the gained mixture was stirred 24 hours.Provide 35mg (21%) " A1 " after the conventional aftertreatment; (M+H) +475; M.p.95 °.
Obtain following compound similarly:
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(N-methyl, N-butyl amino) ethanoyl)-and methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.98 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(morpholine-4-yl) ethanoyl) methylamino] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (" A1-1 "), m.p.86 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(4-hydroxy piperidine-1-yl) ethanoyl)-and methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (" A1-2 "), m.p.78 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(2,6-thebaine-4-yl)-ethanoyl) phenyl methylamino-) }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.137 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(3-cyclohexyl methyl piperidines-1-yl)-ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.104 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(2-diethylamino ethanoyl) methylamino-]-phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.86 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(N-methyl, N-ethylamino) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.113 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(glyoxal ethyline-1-yl) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.171 °; :
1-N-(4-ethynyl phenyl)-2-N-{4-[(2-dimethylamino ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{2-fluoro-4-[(2-dimethylamino ethanoyl)-and methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{5-[(2-dimethylamino ethanoyl) methylamino-] pyridine-2-yl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide.
Embodiment 2
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-acetoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (" A2 ")
2.1 1.146g (4.025mmol) 1 is suspended among the 10ml THF, 0.995g (4.025mmol) EEDQ (=2-oxyethyl group-1,2-dihydroquinoline-1-carboxylic acid, ethyl ester) is added wherein, and at room temperature the gained mixture was stirred 30 minutes.After adding 0.8g (4.027mmol) 4-methylamino aniline (be described in J.Org.Chem.26,1961,1394 in), at room temperature the gained reaction mixture was stirred 18 hours in addition.Carry out obtaining 300mg 1-N-(4-chloro-phenyl-)-2-N-{4-(N-methylamino-) phenyl after the conventional aftertreatment-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (2), (M+H) +390.
2.2 240mg (0.617mmol) (2) is dissolved among the 2ml DCM, and successively 82.92 μ l (0.771mmol) alpha-Acetoxyacetyl chlorides, 62.23 μ l (0.771mmol) pyridines and 0.977mg (0.008mmol) DMAP (=4-(dimethylamino)-pyridine) is added wherein.Subsequently, at room temperature the gained mixture was stirred 18 hours, and carry out conventional aftertreatment, provide 125mg (41%) " A2 ", MS=490 (M+H) +
Obtain following compound similarly:
(2R, 4R)-2-[({[4-(1-[1-(4-chloro-phenyl-formamyl)-4-hydroxyl pyrrolidine-2-yl] and formyl radical } amino) phenyl] the methylamino formyl radical }-methyl) amino]-4-methylvaleric acid methyl esters, m.p.86 °
Figure A20048003769800381
Embodiment 3
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-ethylamino ethanoyl) methylamino-]-phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (" A3 ")
The preparation of (3.1N-4-aminophenyl)-2-chloro-N-methylacetamide (4)
1.0g (4.374mmol) 2-chloro-N-methyl-N-(4-nitrophenyl) ethanamide 3 (being described in Biochem.J.55,1953,839) is dissolved among the 25ml THF, and at room temperature uses 0.5gPt/C (5%)-55.9% water-wet that it is carried out hydrogenation.Provide 4 after the conventional aftertreatment.
3.2 1.146g (4.025mmol) 1 is suspended among the 10ml THF, 0.995g (4.025mmol) EEDQ (=2-oxyethyl group-1,2-dihydroquinoline-1-carboxylic acid, ethyl ester) is added wherein, and at room temperature the gained mixture was stirred 30 minutes.After 0.8g (4.027mmol) 4 addings, at room temperature reaction mixture was stirred 18 hours in addition.Provide 750mg (40%) 1-N-(4-chloro-phenyl)-2-N-{4-[(2-chloracetyl after the conventional aftertreatment) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (" A3a "); (M+H) +466.
3.3 250mg (0.537mmol) " A3a " and 406 μ l (0.806mmol) ethamine (2MTHF solution) are dissolved in the 2ml acetonitrile, 85.4mg (0.806mmol) anhydrous sodium carbonate are added wherein, and under 60 ℃, the gained mixture was stirred 5 hours.Provide 81mg (32%) " A3 " after the conventional aftertreatment; (M+H) +475; M.p.121 °.
Obtain following compound similarly:
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-cyclohexyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.141 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-methylamino-ethanoyl) methylamino-]-phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.145 °;
1-N (4-chloro-phenyl-)-2-N-{4-[(2-sec.-propyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.123.5 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-tertiary butyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2 dicarboxamide, 137 ° of m.p;
1-N-(4-chloro-phenyl-)-2-N-{4[(2-cyclopentyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.130 °;
1-N-(4-chloro-phenyl-)-2-N{4-[(2-cyclopropyl methylamino ethanoyl)-and methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.126 °;
1-N-(4-chloro-phenyl-)-2-N{4-[(2-chloracetyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the chlorine in the 2-dicarboxamide (" A3a ") is substituted and obtains compound:
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-hydroxyacetyl) methylamino-]-phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide.
Embodiment 4
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-methoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (" A4 ")
Under argon gas, with 0.05mmol CuI (5mol%), 1.5mmol 2-methoxyl group ethanamide and 2.03mmol K 3PO 4Put into flask.After adding 1.0ml toluene, with 0.1mmol (10mol%) N, N '-dimethylene diamines and 1.0mmol 1-N-(4-chloro-phenyl-)-2-N-{4-iodophenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide (5), (M+H) +487[is similar to embodiment 3.2 preparations] add wherein, and under 80 ℃, the gained mixture was stirred 12 hours.The cooling and carry out conventional aftertreatment, thereby obtain " A4 "; (M+H) +462; M.p.84 °.
Obtain following compound similarly:
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-oxyethyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxamide, m.p.89 °;
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-propoxy-ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-butoxy ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-ethynyl phenyl)-2-N-{4-[(2-methoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{2-fluoro-4-[(2-methoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{5-[(2-methoxyl group ethanoyl) methylamino-] pyridine-2-yl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide.
Pharmacology data
To the acceptor avidity
Table 1
Compound number FXa-IC 50[nM] TF/FVIIa-IC 50[M]
“A1” 37.0
“A1-1” 54.0 100.0
“A1-2” 37.0 46.0
“A2”
“A3” 17.0 25.0
Following examples relate to pharmaceutical composition:
Embodiment A: injection phial agent
With 2N hydrochloric acid with 100g formula I activeconstituents and 5g Sodium phosphate dibasic the solution in the 3l distilled water to be adjusted to the pH value be 6.5, sterile filtration is transferred in the injection phial, lyophilize and in sealed under aseptic conditions under aseptic condition.Each injection phial contains the 5mg activeconstituents.
Embodiment B: suppository
With the mixture fusion of 20g formula I activeconstituents and 100g soybean lecithin and 1400g theobroma oil, pour in the mould and make its cooling.Each suppository contains the 20mg activeconstituents.
Embodiment C: solution
By 1g formula I activeconstituents, 9.38g NaH 2PO 42H 2O, 28.48gNa 2HPO 412H 2O and 0.1g benzalkonium chloride are prepared into solution in the 940ml distilled water.The pH value is adjusted to 6.8, and makes solution reach 1l, pass through irradiation sterilization.This solution can use with the form of eye drops.
Embodiment D: ointment
Under aseptic condition, 500mg formula I activeconstituents is mixed with 99.5g Vaseline.
Embodiment E: tablet
With usual manner the mixture of 1kg formula I activeconstituents, 4kg lactose, 1.2kg yam starch, 0.2kg talcum and 0.1kg Magnesium Stearate is suppressed to obtain tablet, made every tablet of tablet contain the 10mg activeconstituents.
Embodiment F: coated tablet
Be similar to the embodiment E compressed tablets, carry out dressing by ordinary method with sucrose, yam starch, talcum, tragakanta and dyestuff dressing material subsequently.
Embodiment G: capsule
With ordinary method 2kg formula I activeconstituents is packed in the hard gelatin capsule, make and contain the 20mg activeconstituents in every capsules.
Embodiment H: ampulla
The solution of 1kg formula I activeconstituents in the 60l distilled water is carried out sterile filtration, it is transferred in the ampoule, lyophilize and under aseptic condition in sealed under aseptic conditions.Each ampulla contains the 10mg activeconstituents.

Claims (24)

1. formula I compound,
Wherein
R represent Hal ,-C ≡ C-H ,-C ≡ C-A or OA,
R 1Expression H ,=O, Hal, A, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH ,=N-OA or=CF 2,
X, X ' represent CH, CHal or N separately independently of one another,
Y represents R 4Perhaps Hal,
Ph represents not to be substituted or is replaced or trisubstd phenyls by the single replacement of A, OA, OH or Hal, two,
R 2Expression H, Hal or A,
R 3Expression H or A,
R 4Expression OH, OA, A-COO-, NHA, NHAr, NAA ', Het or-NH-CHR 5-COOR 3,
R 5Expression H, A ,-CHR 3-OH, (CH 2) n-Ph, (CH 2) n-COOH, (CH 2) n-CONH 2, (CH 2) p-NH 2, (CH 2) n-NH (=NH) NH 2, (CH 2) n-Het 1Perhaps (CH 2) n-SR 3,
Het represents to have the monocycle of 1～4 N, O and/or S atom or dicyclo is saturated, unsaturated or aromatic heterocycle, it can not be substituted or by A, OH, OA, CN, COOH, COOA and/or ketonic oxygen (=O) singly replace, two replace or three replace,
Het 1Expression has the monocycle or the Bicyclic heterocycle of 1～4 N, O and/or S atom, and it can not be substituted or is replaced or three replacements by the single replacement of A, OH, OA and/or CN, two,
A, A ' expression independently of one another each other have non-branched-chain alkyl, branched-chain alkyl or the cycloalkyl of 1～12 carbon atom, and wherein 1～7 hydrogen atom can be replaced by fluorine and/or chlorine in addition,
Ar represents not to be substituted or by Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3, CON (R 3) 2, NR 3COA, NR 3CON (R 3) 2, NR 3SO 2A, COR 3, SO 2N (R 3) 2, S (O) nA ,-[C (R 3) 2] n-COOR 3Perhaps-O-[C (R 3) 2] p-COOR 3Single replacement, two replaces or trisubstituted naphthyl, xenyl or phenyl,
Hal represents F, Cl, Br or I,
N represents 0,1,2 or 3,
P represents 1,2,3,4 or 5,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
2. according to the compound of claim 1, wherein:
R represent Hal or-C ≡ C-H,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
3. according to the compound of claim 1 or 2, wherein:
R 1Expression H ,=O, Hal, A, OH or OA,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
4. according to one or multinomial compound in the claim 1～3, wherein:
R 1Expression OH,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
5. according to one or multinomial compound in the claim 1～4, wherein:
X represents CH or N,
X ' expression CH,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
6. according to one or multinomial compound in the claim 1～5, wherein:
R 2Expression H or Hal,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
7. according to one or multinomial compound in the claim 1～6, wherein:
R 3Expression H or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
8. according to one or multinomial compound in the claim 1～7, wherein:
Het represents to have saturated, the unsaturated or aromatic heterocycle of monocycle of 1～2 N and/or O atom, and it can not be substituted or is replaced or three replacements by A, OH and/or the single replacement of OA, two,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
9. according to one or multinomial compound in the claim 1～8, wherein:
Het represents furyl, thienyl, pyrryl, imidazolyl, pyridyl, pyrimidyl, pyrazolyl, thiazolyl, indyl, pyrrolidyl, piperidyl, morpholinyl or piperazinyl, they are not substituted separately or are replaced or three replacements by A, OH and/or the single replacement of OA, two
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
10. according to one or multinomial compound in the claim 1～9, wherein:
Het 1Expression has the unsubstituted monocycle or the Bicyclic heterocycle of 1～2 N, O and/or S atom,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
11. according to one or multinomial compound in the claim 1～10, wherein:
R 5Expression H or A,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
12. according to one or multinomial compound in the claim 1～11, wherein:
Ar represents not to be substituted or by Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3Perhaps CON (R 3) 2Single replacement, two replaces or trisubstituted naphthyl or phenyl,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
13. according to one or multinomial compound in the claim 1～12, wherein:
Ar represents phenyl,
And pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
14. according to one or multinomial compound in the claim 1～13, wherein:
R represent Hal or-C ≡ C-H,
R 1Expression OH,
X represents CH or N,
X ' expression CH,
Y represents R 4Perhaps Hal,
R 2Expression H or Hal,
R 3Expression has the alkyl of 1,2,3,4,5 or 6 carbon atom,
R 4Expression OH, OA, A-COO-, NHA, NHAr, NAA ', Het ,-NH-CHR 5-COOR 3Perhaps-NH-CHR 5-COOH,
R 5Expression H or A,
Het represents to have saturated, the unsaturated or aromatic heterocycle of monocycle of 1～2 N and/or O atom, and it can not be substituted or is replaced or three replacements by A, OH and/or the single replacement of OA, two,
A, A ' expression independently of one another each other have non-branched-chain alkyl, branched-chain alkyl or the cycloalkyl of 1～12 carbon atom, and wherein 1～7 hydrogen atom can be replaced by fluorine and/or chlorine in addition,
Hal represents F, Cl, Br or I,
N represents 0,1,2 or 3,
P represents 1,2,3,4 or 5,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
15. according to one or multinomial formula Ia compound in the claim 1～14,
Figure A2004800376980005C1
Wherein
R represent Hal ,-C ≡ C-H,
R 1Expression OH,
X represents CH or N,
X ' expression CH,
Y represents R 4Perhaps Hal,
R 2Expression H or Hal,
R 3Expression has the alkyl of 1,2,3,4,5 or 6 carbon atom,
R 4Expression OH, OA, A-COO-, NHA, NAA ', Het, NH-CHR 5-COOR 3Perhaps-NH-CHR 5-COOH,
R 5Expression H or A,
Het represents to have saturated, the unsaturated or aromatic heterocycle of monocycle of 1～2 N and/or O atom, and it can not be substituted or is replaced or three replacements by A, OH and/or the single replacement of OA, two,
A, A ' represent to have non-branched-chain alkyl, branched-chain alkyl or the cycloalkyl of 1～12 carbon atom separately independently of one another, and wherein 1～7 hydrogen atom can be replaced by fluorine and/or chlorine in addition,
Hal represents F, Cl, Br or I,
N represents 0,1,2 or 3,
P represents 1,2,3,4 or 5,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
16. the compound according to claim 1 is selected from:
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-dimethylamino ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(N-methyl, N-butyl amino) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(morpholine-4-yl) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(4-hydroxy piperidine-1-yl) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(2,6-thebaine-4-yl) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(3-cyclohexyl methyl piperidines-1-yl) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-diethylamino ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(N-methyl, N-ethylamino) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-(glyoxal ethyline-1-yl) ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-ethynyl phenyl)-2-N-{4-[(2-dimethylamino ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{2-fluoro-4-[(2-methylamino ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{5-[(2-dimethylamino ethanoyl) methylamino-] pyridine-2-yl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-acetoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
(2R, 4R)-2-[({[4-(1-[1-(4-chloro-phenyl-formamyl)-4-hydroxyl pyrrolidine-2-yl] and formyl radical } amino) phenyl] the methylamino formyl radical } methyl) amino]-4-methylvaleric acid methyl esters,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-ethylamino ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-chloracetyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-cyclohexyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-methylamino-ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-sec.-propyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-tertiary butyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-cyclopentyl glycyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-cyclopropyl methylamino-ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-hydroxyacetyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-methoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-oxyethyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-propoxy-ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{4-[(2-butoxy ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-ethynyl phenyl)-2-N-{4-[(2-methoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{2-fluoro-4-[(2-methoxyl group ethanoyl) methylamino-] phenyl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
1-N-(4-chloro-phenyl-)-2-N-{5-[(2-methoxyl group ethanoyl) methylamino-] pyridine-2-yl }-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-dicarboxamide,
With and pharmaceutically available derivative, solvate, salt and steric isomer, comprise the mixture of their various ratios.
17. preparation according to the formula I compound of claim 1～16 with and the method for available derivative, solvate, salt and steric isomer pharmaceutically, it is characterized in that:
A) make formula II compound
Wherein R, R 1, R 2, X and X ' as defined in claim 1,
With the reaction of formula III compound,
Wherein
Y and R 3As defined in claim 1,
Perhaps
B) make formula IV compound
Wherein R, R 1, R 2, R 3, X and X ' as defined in claim 1,
With the reaction of formula V compound,
Figure A2004800376980009C3
Wherein Y as defined in claim 1, and
L represents the OH group that Cl, Br, I or free or reactive functional are modified, perhaps
C) make formula VI compound
Wherein R and R 1As defined in claim 1, and
L represents the OH group that Cl, Br, I or free or reactive functional are modified, with the reaction of formula VII compound,
R wherein 2, R 3, X, X ' and Y as defined in claim 1,
And/or
Alkali or the sour salt that is converted into it with formula I.
18. as coagulation factor xa inhibitors according to one or multinomial formula I compound in the claim 1～16.
19. as proconvertin a inhibitor according to one or multinomial formula I compound in the claim 1～16.
20. medicine, contain at least a according to one or multinomial formula I compound in the claim 1～16 and/or its pharmaceutically available derivative, solvate and steric isomer, the mixture that comprises its all proportions, and optional vehicle and/or the auxiliary of containing.
21. medicine, comprise at least a according to one or multinomial formula I compound in the claim 1～16 and/or its pharmaceutically available derivative, solvate and steric isomer, comprise the mixture of its all proportions, and comprise at least a other medicines activeconstituents.
22. according to one or multinomial compound and/or acceptable salt of its physiology and the purposes of solvate in the medicine of the following disease of preparation treatment in the claim 1～16: thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or metastases.
23. the packaging kit of forming by following independent packing (test kit):
(a) significant quantity according in one of the claim 1～16 or multinomial formula I compound and/or its pharmaceutically available derivative, solvate and steric isomer, comprise its all proportions mixture and
(b) the other medicines activeconstituents of significant quantity.
24. according to one or multinomial formula I compound in the claim 1～16 and/or its pharmaceutically available derivative, solvate and steric isomer, the mixture that comprises its all proportions is combined in the purposes for preparing in the medicine for the treatment of following disease with at least a other medicines activeconstituents: thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or metastases.
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